ApOE effects on neuron signaling and function via ApoER2

描述（由申请人提供）：载脂蛋白E是阿尔茨海默病最强的遗传风险因子，其在大脑中的许多作用由特定的载脂蛋白E受体介导。在过去的几年里，我们已经确定了apoE和apoE受体在大脑中的各种信号作用，并研究了它们如何影响神经元生理学和动物行为。在这个提议中，我们专注于最有趣的突触apoE受体之一，ApoER 2，及其作为突触信号分子的功能机制。此外，我们正在使用APOE靶向替代小鼠，研究三种人类apoE亚型与ApoER 2相互作用的差异。该项目是两个研究中心的两名研究人员之间的合作，以利用ApoER 2信号传导和不同实验技术的共同兴趣。通过进行体外和体内实验，我们将能够测试体内与体外发现的相关性，并设计体外实验来定义体内发现的机制。有四个具体目标;前三个研究了apoE亚型通过ApoER 2的神经元信号传导功能;最后一个研究了这些功能如何有助于神经变性的致病过程。1.我们将确定三种人类apoE异构体对神经元结构和突触功能的体内影响; 2.我们将明确ApoER 2在体外对神经元信号传导的作用机制; 3.我们将定义ApoER 2如何影响体内神经元信号传导;和4.我们将把这些基本发现转化为两种方法，以防止阿尔茨海默病病理变化模型中的突触丢失。这些相互联系和互补的目标将使我们能够确定apoE亚型在正常神经元功能中的重要作用，这可能有助于AD的相关风险。这些实验还解决了apoE受体在神经元信号传导中的新功能，定义了这些受体改变突触功能的机制。他们还探索了受体聚集在正常受体信号传导机制中的作用。最后，他们将测试关于APOE基因型如何改变阿尔茨海默病风险的两个重要假设，将JNK激活和ApoER 2受体聚集的初步发现转化为预防与神经变性相关的突触功能障碍的方法。 公共卫生相关性：阿尔茨海默氏病已经影响了美国500多万人，随着老年人数量的增加，这一数字将在40年内增加两倍。APOE是阿尔茨海默病最强的遗传风险因素，影响了一半以上的病例，但我们不知道它如何影响疾病。这项拟议的研究将解决apoE在大脑中的作用，并确定它可能影响阿尔茨海默病的方式。

DESCRIPTION (provided by applicant): APOE is the strongest genetic risk factor for Alzheimer's disease and many of its actions in the brain are mediated by specific apoE receptors. Over the past several years, we have defined various signaling roles for apoE and apoE receptors in the brain, and examined how they affect neuronal physiology and animal behavior. In this proposal, we are focusing on one of the most interesting synaptic apoE receptors, ApoER2, and its mechanism of function as a synaptic signaling molecule. Furthermore, we are addressing how the three human apoE isoforms differ in their interactions with ApoER2, using APOE targeted replacement mice. This project is a collaboration between two investigators at two sites, to make use of common interests in ApoER2 signaling and diverse experimental techniques. By conducting both in vitro and in vivo experiments, we will be able to test the in vivo relevance to in vitro findings and design in vitro experiments to define mechanisms for in vivo findings. There are four specific aims; the first three examine the neuronal signaling functions of apoE isoforms via ApoER2; the last one examines how those functions may contribute to pathogenic processes of neurodegeneration. 1. We will determine the in vivo effects of the three human apoE isoforms on neuronal structure and synaptic function; 2. We will define mechanisms of ApoER2 effects on neuronal signaling in vitro; 3. We will define how ApoER2 affects neuronal signaling in vivo; and 4. We will translate these basic findings into two approaches to protecting against synaptic loss in models with Alzheimer's disease pathological changes. These connected and complementary aims will allow us to define important roles of apoE isoforms in normal neuronal function, which may contribute to the associated risk of AD. These experiments also address new functions of apoE receptors in neuronal signaling, defining mechanisms by which these receptors alter synaptic function. They also explore the role of receptor clustering in normal receptor signaling mechanisms. Finally, they will test two important hypotheses about how APOE genotype alters the risk of Alzheimer's disease, translating preliminary findings about JNK activation and ApoER2 receptor clustering into approaches to prevent the synaptic dysfunction associated with neurodegeneration. PUBLIC HEALTH RELEVANCE: Alzheimer's disease affects over 5 million people in the USA already, and the numbers will triple in 40 years giving the increasing numbers of aged citizens. APOE is the strongest genetic risk factor for Alzheimer's disease, influencing over half of all cases, but we do not know how it influences the disease. This proposed research will address the actions of apoE in the brain, and identify ways that it could be affecting Alzheimer's disease.